Figure 1.
Schematic model for the Nav1.3/FGF14 protein interactions that regulate fast and slow recovery from inactivation and determine Nav availability during pulse trains of varying frequency in rodent chromaffin cells.(A) A simplified schematic diagram of Nav1.3 channel transitions between closed, open, fast, and long-term inactivated states derived from Dover et al. (2010), Milescu et al. (2010), Venkatesan et al. (2014), and the two articles from Martinez-Espinosa et al. (2021a, 2021b). The endogenous IFM inactivation particle in the DIII–DIV cytoplasmic loop (red oval) and the N terminus of the FGF14 protein (blue oval), with its core domain (white oval) tethered to the C terminus of the channel, compete for access within the pore to inactivate the open channel during step depolarization. The two inactivation particles compete for docking within the open pore (fast and long-term inactivated states). The onset of fast and long-term inactivation is comparably fast (a few milliseconds; up and down red arrows in right panels). Recovery from long-term inactivation is slow (50–400 ms) and may occur while the channel is open (black arrow) or closed (not shown). Recovery from fast inactivation is fast and proceeds through the closed state of the channel (horizontal and up red arrows; Kuo and Bean, 1994). The closed and fast inactivated states preceding the two indicated to the left are not shown for simplicity (see Goldfarb, 2012). (B) Nav1.3 currents (blue traces) recorded from mouse chromaffin cells during voltage-clamp commands with a 10-pulse train of increasing frequency. Nav current amplitudes are drawn after having interpolated the data of Figs. 8, 10, and S1 of Martinez-Espinosa et al. (2021a). Steps of 5 ms to 0 mV from −80 mV holding potentials (Vh) were applied at 1, 4, or 10 Hz. Nav1.3 current amplitudes decrease progressively during the 10-pulse trains. At 1 Hz the amplitude attenuation is nearly detectable, while at 10 Hz it is remarkable. The percentage of occupancies in the fast and slow recovery pathways calculated by Martinez-Espinosa et al. (2021a, 2021b) are indicated in red (fast recovery) and black (slow recovery). After terminating the first depolarizing step, Nav channels are equally distributed (50%) in both the fast and slow pathway. With increasing frequency, Nav availability is strongly attenuated. Nav channels accumulate in the slow recovery pathway during the pulse train: 52% at 1 Hz, 68% at 4 Hz, and 80% at 10 Hz.

Schematic model for the Nav1.3/FGF14 protein interactions that regulate fast and slow recovery from inactivation and determine Nav availability during pulse trains of varying frequency in rodent chromaffin cells.(A) A simplified schematic diagram of Nav1.3 channel transitions between closed, open, fast, and long-term inactivated states derived from Dover et al. (2010), Milescu et al. (2010), Venkatesan et al. (2014), and the two articles from Martinez-Espinosa et al. (2021a, 2021b). The endogenous IFM inactivation particle in the DIII–DIV cytoplasmic loop (red oval) and the N terminus of the FGF14 protein (blue oval), with its core domain (white oval) tethered to the C terminus of the channel, compete for access within the pore to inactivate the open channel during step depolarization. The two inactivation particles compete for docking within the open pore (fast and long-term inactivated states). The onset of fast and long-term inactivation is comparably fast (a few milliseconds; up and down red arrows in right panels). Recovery from long-term inactivation is slow (50–400 ms) and may occur while the channel is open (black arrow) or closed (not shown). Recovery from fast inactivation is fast and proceeds through the closed state of the channel (horizontal and up red arrows; Kuo and Bean, 1994). The closed and fast inactivated states preceding the two indicated to the left are not shown for simplicity (see Goldfarb, 2012). (B) Nav1.3 currents (blue traces) recorded from mouse chromaffin cells during voltage-clamp commands with a 10-pulse train of increasing frequency. Nav current amplitudes are drawn after having interpolated the data of Figs. 8, 10, and S1 of Martinez-Espinosa et al. (2021a). Steps of 5 ms to 0 mV from −80 mV holding potentials (Vh) were applied at 1, 4, or 10 Hz. Nav1.3 current amplitudes decrease progressively during the 10-pulse trains. At 1 Hz the amplitude attenuation is nearly detectable, while at 10 Hz it is remarkable. The percentage of occupancies in the fast and slow recovery pathways calculated by Martinez-Espinosa et al. (2021a, 2021b) are indicated in red (fast recovery) and black (slow recovery). After terminating the first depolarizing step, Nav channels are equally distributed (50%) in both the fast and slow pathway. With increasing frequency, Nav availability is strongly attenuated. Nav channels accumulate in the slow recovery pathway during the pulse train: 52% at 1 Hz, 68% at 4 Hz, and 80% at 10 Hz.

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